Depth- and range-dependent variation in the performance of aquatic telemetry systems: Understanding and predicting the susceptibility of acoustic tag-receiver pairs to close proximity detection interference

BACKGROUND: Passive acoustic telemetry using coded transmitter tags and stationary receivers is a popular method for tracking movements of aquatic animals. Understanding the performance of these systems is important in array design and in analysis. Close proximity detection interference (CPDI) is a condition where receivers fail to reliably detect tag transmissions. CPDI generally occurs when the tag and receiver are near one another in acoustically reverberant settings. Here we confirm transmission multipaths reflected off the environment arriving at a receiver with sufficient delay relative to the direct signal cause CPDI. We propose a ray-propagation based model to estimate the arrival of energy via multipaths to predict CPDI occurrence, and we show how deeper deployments are particularly susceptible. METHODS: A series of experiments were designed to develop and validate our model. Deep (300 m) and shallow (25 m) ranging experiments were conducted using Vemco V13 acoustic tags and VR2-W receivers. Probabilistic modeling of hourly detections was used to estimate the average distance a tag could be detected. A mechanistic model for predicting the arrival time of multipaths was developed using parameters from these experiments to calculate the direct and multipath path lengths. This model was retroactively applied to the previous ranging experiments to validate CPDI observations. Two additional experiments were designed to validate predictions of CPDI with respect to combinations of deployment depth and distance. Playback of recorded tags in a tank environment was used to confirm multipaths arriving after the receiver\u27s blanking interval cause CPDI effects. RESULTS: Analysis of empirical data estimated the average maximum detection radius (AMDR), the farthest distance at which 95% of tag transmissions went undetected by receivers, was between 840 and 846 m for the deep ranging experiment across all factor permutations. From these results, CPDI was estimated within a 276.5 m radius of the receiver. These empirical estimations were consistent with mechanistic model predictions. CPDI affected detection at distances closer than 259-326 m from receivers. AMDR determined from the shallow ranging experiment was between 278 and 290 m with CPDI neither predicted nor observed. Results of validation experiments were consistent with mechanistic model predictions. Finally, we were able to predict detection/nondetection with 95.7% accuracy using the mechanistic model\u27s criterion when simulating transmissions with and without multipaths. DISCUSSION: Close proximity detection interference results from combinations of depth and distance that produce reflected signals arriving after a receiver\u27s blanking interval has ended. Deployment scenarios resulting in CPDI can be predicted with the proposed mechanistic model. For deeper deployments, sea-surface reflections can produce CPDI conditions, resulting in transmission rejection, regardless of the reflective properties of the seafloor

Rituximab versus tocilizumab and B-cell status in TNF-alpha inadequate-responder rheumatoid arthritis patients: the R4-RA RCT

BackgroundAlthough biological therapies have transformed the outlook for those with rheumatoid arthritis, there is a lack of any meaningful response in approximately 40% of patients. The role of B cells in rheumatoid arthritis pathogenesis is well recognised and is supported by the clinical efficacy of the B-cell-depleting agent rituximab (MabThera, F. Hoffman La-Roche Ltd, Basel, Switzerland). Rituximab is licensed for use in rheumatoid arthritis following failure of conventional synthetic disease-modifying antirheumatic drugs and tumour necrosis factor inhibitor therapy. However, over 50% of patients show low/absent synovial B-cell infiltration, suggesting that, in these patients, inflammation is driven by alternative cell types. This prompted us to test the hypothesis that, in synovial biopsy B-cell-poor patients, tocilizumab (RoActemra, F. Hoffman La-Roche Ltd, Basel, Switzerland) (targeting interleukin 6) is superior to rituximab (targeting CD20+/B cells).DesignThe R4–RA (A Randomised, open-labelled study in anti-TNFalpha inadequate responders to investigate the mechanisms for Response, Resistance to Rituximab versus Tocilizumab in Rheumatoid Arthritis patients) trial is a 48-week Phase IV, open-label, randomised controlled trial conducted in 19 European centres that recruited patients failing on or intolerant to conventional synthetic disease-modifying antirheumatic drug therapy and at least one tumour necrosis factor inhibitor.ParticipantsSynovial tissue was obtained at trial entry and classified histologically as B-cell rich or B-cell poor to inform balanced stratification. Patients were randomised on a 1 : 1 basis to receive standard therapy with rituximab or tocilizumab. B-cell-poor/-rich molecular classification was also carried out. The study was powered to test the superiority of tocilizumab over rituximab at 16 weeks in the B-cell-poor population.Main outcome measuresThe primary end point was defined as an improvement in the Clinical Disease Activity Index (CDAI) score of ≥ 50% from baseline. In addition, patients were considered to be non-responders if they did not reach an improvement in CDAI score of ≥ 50% and a CDAI score of ResultsIn total, 164 patients were randomised: 83 patients received rituximab and 81 received tocilizumab. Eighty-one out of 83 rituximab patients and 73 out of 81 tocilizumab patients completed treatment up to week 16 (primary end point). Baseline characteristics were comparable between the treatment groups. In the histologically classified B-cell-poor population (n = 79), no significant difference was observed in the primary outcome, an improvement in CDAI score of ≥ 50% from baseline (risk ratio 1.25, 95% confidence interval 0.80 to 1.96). A supplementary analysis of the CDAI-MTR, however, did reach statistical significance (risk ratio 1.96, 95% confidence interval 1.01 to 3.78). In addition, when B-cell-poor classification was determined molecularly, both the primary end point and the CDAI-MTR were statistically significant (risk ratio 1.72, 95% confidence interval 1.02 to 2.91, and risk ratio 4.12, 95% confidence interval 1.55 to 11.01, respectively). Moreover, a larger number of secondary end points achieved significance when classified molecularly than when classified histologically. In the B-cell-rich population, there was no significant difference between treatments in the majority of both primary and secondary end points. There were more adverse events and serious adverse events, such as infections, in the tocilizumab group than in the rituximab group.ConclusionTo our knowledge, this is the first biopsy-based, multicentre, randomised controlled trial of rheumatoid arthritis. We were unable to demonstrate that tocilizumab was more effective than rituximab in patients with a B-cell-poor pathotype in our primary analysis. However, superiority was shown in most of the supplementary and secondary analyses using a molecular classification. These analyses overcame possible unavoidable weaknesses in our original study plan, in which the histological method of determining B-cell status may have misclassified some participants and our chosen primary outcome was insufficiently sensitive. Given the significant results observed using the molecular classification, future research will focus on refining this stratification method and evaluating its clinical utility.Trial registrationCurrent Controlled Trials ISRCTN97443826.FundingThis project was funded by the Efficacy and Mechanism Evaluation (EME) programme, a Medical Research Council and National Institute for Health and Care Research (NIHR) partnership. This will be published in full in Efficacy and Mechanism Evaluation; Vol. 9, No. 7. See the NIHR Journals Library website for further project information

History of migraine and volume of brain infarcts: The italian project on stroke at young age (IPSYS)

BACKGROUND AND PURPOSE: Migraine has been shown to increase cerebral excitability, promote rapid infarct expansion into tissue with perfusion deficits, and result in larger infarcts in animal models of focal cerebral ischemia. Whether these effects occur in humans has never been properly investigated. METHODS: In a series of consecutive patients with acute ischemic stroke, enrolled in the setting of the Italian Project on Stroke at Young Age, we assessed acute as well as chronic infarct volumes by volumetric magnetic resonance imaging, and compared these among different subgroups identified by migraine status. RESULTS: A cohort of 591 patients (male, 53.8%; mean age, 37.5±6.4 years) qualified for the analysis. Migraineurs had larger acute infarcts than non-migraineurs (median, 5.9 cm3 [interquartile range (IQR), 1.4 to 15.5] vs. 2.6 cm3 [IQR, 0.8 to 10.1], P<0.001), and the largest volumes were observed in patients with migraine with aura (median, 9.0 cm3 [IQR, 3.4 to 16.6]). In a linear regression model, migraine was an independent predictor of increased log (acute infarct volumes) (median ratio [MR], 1.64; 95% confidence interval [CI], 1.22 to 2.20), an effect that was more prominent for migraine with aura (MR, 2.92; 95% CI, 1.88 to 4.54). CONCLUSION: s These findings reinforce the experimental observation of larger acute cerebral infarcts in migraineurs, extend animal data to human disease, and support the hypothesis of increased vulnerability to ischemic brain injury in people suffering migraine

B Cell Synovitis and Clinical Phenotypes in Rheumatoid Arthritis: Relationship to Disease Stages and Drug Exposure.

OBJECTIVE: To define the relationship of synovial B cells to clinical phenotypes at different stages of disease evolution and drug exposure in rheumatoid arthritis (RA). METHODS: Synovial biopsy specimens and demographic and clinical data were collected from 2 RA cohorts (n = 329), one of patients with untreated early RA (n = 165) and one of patients with established RA with an inadequate response to tumor necrosis factor inhibitors (TNFi-IR; n = 164). Synovial tissue was subjected to hematoxylin and eosin and immunohistochemical staining and semiquantitative assessment for the degree of synovitis (on a scale of 0-9) and of CD20+ B cell infiltrate (on a scale of 0-4). B cell scores were validated by digital image analysis and B cell lineage-specific transcript analysis (RNA-Seq) in the early RA (n = 91) and TNFi-IR (n = 127) cohorts. Semiquantitative CD20 scores were used to classify patients as B cell rich (≥2) or B cell poor (<2). RESULTS: Semiquantitative B cell scores correlated with digital image analysis quantitative measurements and B cell lineage-specific transcripts. B cell-rich synovitis was present in 35% of patients in the early RA cohort and 47.7% of patients in the TNFi-IR cohort (P = 0.025). B cell-rich patients showed higher levels of disease activity and seropositivity for rheumatoid factor and anti-citrullinated protein antibody in early RA but not in established RA, while significantly higher histologic synovitis scores in B cell-rich patients were demonstrated in both cohorts. CONCLUSION: We describe a robust semiquantitative histologic B cell score that closely replicates the quantification of B cells by digital or molecular analyses. Our findings indicate an ongoing B cell-rich synovitis, which does not seem to be captured by standard clinimetric assessment, in a larger proportion of patients with established RA than early RA

Rituximab versus tocilizumab in rheumatoid arthritis: synovial biopsy-based biomarker analysis of the phase 4 R4RA randomized trial

Patients with rheumatoid arthritis (RA) receive highly targeted biologic therapies without previous knowledge of target expression levels in the diseased tissue. Approximately 40% of patients do not respond to individual biologic therapies and 5–20% are refractory to all. In a biopsy-based, precision-medicine, randomized clinical trial in RA (R4RA; n = 164), patients with low/absent synovial B cell molecular signature had a lower response to rituximab (anti-CD20 monoclonal antibody) compared with that to tocilizumab (anti-IL6R monoclonal antibody) although the exact mechanisms of response/nonresponse remain to be established. Here, in-depth histological/molecular analyses of R4RA synovial biopsies identify humoral immune response gene signatures associated with response to rituximab and tocilizumab, and a stromal/fibroblast signature in patients refractory to all medications. Post-treatment changes in synovial gene expression and cell infiltration highlighted divergent effects of rituximab and tocilizumab relating to differing response/nonresponse mechanisms. Using ten-by-tenfold nested cross-validation, we developed machine learning algorithms predictive of response to rituximab (area under the curve (AUC) = 0.74), tocilizumab (AUC = 0.68) and, notably, multidrug resistance (AUC = 0.69). This study supports the notion that disease endotypes, driven by diverse molecular pathology pathways in the diseased tissue, determine diverse clinical and treatment–response phenotypes. It also highlights the importance of integration of molecular pathology signatures into clinical algorithms to optimize the future use of existing medications and inform the development of new drugs for refractory patients

Stratification of biological therapies by pathobiology in biologic-naive patients with rheumatoid arthritis (STRAP and STRAP-EU): two parallel, open-label, biopsy-driven, randomised trials

Background: Despite highly effective targeted therapies for rheumatoid arthritis, about 40% of patients respond poorly, and predictive biomarkers for treatment choices are lacking. We did a biopsy-driven trial to compare the response to rituximab, etanercept, and tocilizumab in biologic-naive patients with rheumatoid arthritis stratified for synovial B cell status. Methods: STRAP and STRAP-EU were two parallel, open-label, biopsy-driven, stratified, randomised, phase 3 trials done across 26 university centres in the UK and Europe. Biologic-naive patients aged 18 years or older with rheumatoid arthritis based on American College of Rheumatology (ACR)–European League Against Rheumatism classification criteria and an inadequate response to conventional synthetic disease-modifying antirheumatic drugs (DMARDs) were included. Following ultrasound-guided synovial biopsy, patients were classified as B cell poor or B cell rich according to synovial B cell signatures and randomly assigned (1:1:1) to intravenous rituximab (1000 mg at week 0 and week 2), subcutaneous tocilizumab (162 mg per week), or subcutaneous etanercept (50 mg per week). The primary outcome was the 16-week ACR20 response in the B cell-poor, intention-to-treat population (defined as all randomly assigned patients), with data pooled from the two trials, comparing etanercept and tocilizumab (grouped) versus rituximab. Safety was assessed in all patients who received at least one dose of study drug. These trials are registered with the EU Clinical Trials Register, 2014-003529-16 (STRAP) and 2017-004079-30 (STRAP-EU). Findings: Between June 8, 2015, and July 4, 2019, 226 patients were randomly assigned to etanercept (n=73), tocilizumab (n=74), and rituximab (n=79). Three patients (one in each group) were excluded after randomisation because they received parenteral steroids in the 4 weeks before recruitment. 168 (75%) of 223 patients in the intention-to-treat population were women and 170 (76%) were White. In the B cell-poor population, ACR20 response at 16 weeks (primary endpoint) showed no significant differences between etanercept and tocilizumab grouped together and rituximab (46 [60%] of 77 patients vs 26 [59%] of 44; odds ratio 1·02 [95% CI 0·47–2·17], p=0·97). No differences were observed for adverse events, including serious adverse events, which occurred in six (6%) of 102 patients in the rituximab group, nine (6%) of 108 patients in the etanercept group, and three (4%) of 73 patients in the tocilizumab group (p=0·53). Interpretation: In this biologic-naive population of patients with rheumatoid arthrtitis, the dichotomic classification into synovial B cell poor versus rich did not predict treatment response to B cell depletion with rituximab compared with alternative treatment strategies. However, the lack of response to rituximab in patients with a pauci-immune pathotype and the higher risk of structural damage progression in B cell-rich patients treated with rituximab warrant further investigations into the ability of synovial tissue analyses to inform disease pathogenesis and treatment response. Funding: UK Medical Research Council and Versus Arthritis

Stratification of biological therapies by pathobiology in biologic-naive patients with rheumatoid arthritis (STRAP and STRAP-EU): two parallel, open-label, biopsy-driven, randomised trials

BACKGROUND: Despite highly effective targeted therapies for rheumatoid arthritis, about 40% of patients respond poorly, and predictive biomarkers for treatment choices are lacking. We did a biopsy-driven trial to compare the response to rituximab, etanercept, and tocilizumab in biologic-naive patients with rheumatoid arthritis stratified for synovial B cell status. METHODS: STRAP and STRAP-EU were two parallel, open-label, biopsy-driven, stratified, randomised, phase 3 trials done across 26 university centres in the UK and Europe. Biologic-naive patients aged 18 years or older with rheumatoid arthritis based on American College of Rheumatology (ACR)–European League Against Rheumatism classification criteria and an inadequate response to conventional synthetic disease-modifying antirheumatic drugs (DMARDs) were included. Following ultrasound-guided synovial biopsy, patients were classified as B cell poor or B cell rich according to synovial B cell signatures and randomly assigned (1:1:1) to intravenous rituximab (1000 mg at week 0 and week 2), subcutaneous tocilizumab (162 mg per week), or subcutaneous etanercept (50 mg per week). The primary outcome was the 16-week ACR20 response in the B cell-poor, intention-to-treat population (defined as all randomly assigned patients), with data pooled from the two trials, comparing etanercept and tocilizumab (grouped) versus rituximab. Safety was assessed in all patients who received at least one dose of study drug. These trials are registered with the EU Clinical Trials Register, 2014-003529-16 (STRAP) and 2017-004079-30 (STRAP-EU). FINDINGS: Between June 8, 2015, and July 4, 2019, 226 patients were randomly assigned to etanercept (n=73), tocilizumab (n=74), and rituximab (n=79). Three patients (one in each group) were excluded after randomisation because they received parenteral steroids in the 4 weeks before recruitment. 168 (75%) of 223 patients in the intention-to-treat population were women and 170 (76%) were White. In the B cell-poor population, ACR20 response at 16 weeks (primary endpoint) showed no significant differences between etanercept and tocilizumab grouped together and rituximab (46 [60%] of 77 patients vs 26 [59%] of 44; odds ratio 1·02 [95% CI 0·47–2·17], p=0·97). No differences were observed for adverse events, including serious adverse events, which occurred in six (6%) of 102 patients in the rituximab group, nine (6%) of 108 patients in the etanercept group, and three (4%) of 73 patients in the tocilizumab group (p=0·53). INTERPRETATION: In this biologic-naive population of patients with rheumatoid arthrtitis, the dichotomic classification into synovial B cell poor versus rich did not predict treatment response to B cell depletion with rituximab compared with alternative treatment strategies. However, the lack of response to rituximab in patients with a pauci-immune pathotype and the higher risk of structural damage progression in B cell-rich patients treated with rituximab warrant further investigations into the ability of synovial tissue analyses to inform disease pathogenesis and treatment response. FUNDING: UK Medical Research Council and Versus Arthritis

Recurrent Ischemic Stroke and Bleeding in Patients With Atrial Fibrillation Who Suffered an Acute Stroke While on Treatment With Nonvitamin K Antagonist Oral Anticoagulants: The RENO-EXTEND Study

Background: In patients with atrial fibrillation who suffered an ischemic stroke while on treatment with nonvitamin K antagonist oral anticoagulants, rates and determinants of recurrent ischemic events and major bleedings remain uncertain. Methods: This prospective multicenter observational study aimed to estimate the rates of ischemic and bleeding events and their determinants in the follow-up of consecutive patients with atrial fibrillation who suffered an acute cerebrovascular ischemic event while on nonvitamin K antagonist oral anticoagulant treatment. Afterwards, we compared the estimated risks of ischemic and bleeding events between the patients in whom anticoagulant therapy was changed to those who continued the original treatment. Results: After a mean follow-up time of 15.0±10.9 months, 192 out of 1240 patients (15.5%) had 207 ischemic or bleeding events corresponding to an annual rate of 13.4%. Among the events, 111 were ischemic strokes, 15 systemic embolisms, 24 intracranial bleedings, and 57 major extracranial bleedings. Predictive factors of recurrent ischemic events (strokes and systemic embolisms) included CHA2DS2-VASc score after the index event (odds ratio [OR], 1.2 [95% CI, 1.0–1.3] for each point increase; P=0.05) and hypertension (OR, 2.3 [95% CI, 1.0–5.1]; P=0.04). Predictive factors of bleeding events (intracranial and major extracranial bleedings) included age (OR, 1.1 [95% CI, 1.0–1.2] for each year increase; P=0.002), history of major bleeding (OR, 6.9 [95% CI, 3.4–14.2]; P=0.0001) and the concomitant administration of an antiplatelet agent (OR, 2.8 [95% CI, 1.4–5.5]; P=0.003). Rates of ischemic and bleeding events were no different in patients who changed or not changed the original nonvitamin K antagonist oral anticoagulants treatment (OR, 1.2 [95% CI, 0.8–1.7]). Conclusions: Patients suffering a stroke despite being on nonvitamin K antagonist oral anticoagulant therapy are at high risk of recurrent ischemic stroke and bleeding. In these patients, further research is needed to improve secondary prevention by investigating the mechanisms of recurrent ischemic stroke and bleeding

Association of Toll-like receptor 7 variants with life-threatening COVID-19 disease in males: findings from a nested case-control study

Background: Recently, loss-of-function variants in TLR7 were identified in two families in which COVID-19 segregates like an X-linked recessive disorder environmentally conditioned by SARS-CoV-2. We investigated whether the two families represent the tip of the iceberg of a subset of COVID-19 male patients.Methods: This is a nested case-control study in which we compared male participants with extreme phenotype selected from the Italian GEN-COVID cohort of SARS-CoV-2-infected participants (&lt;60y, 79 severe cases versus 77 control cases). We applied the LASSO Logistic Regression analysis, considering only rare variants on young male subsets with extreme phenotype, picking up TLR7 as the most important susceptibility gene.Results: Overall, we found TLR7 deleterious variants in 2.1% of severely affected males and in none of the asymptomatic participants. The functional gene expression profile analysis demonstrated a reduction in TLR7-related gene expression in patients compared with controls demonstrating an impairment in type I and II IFN responses.Conclusion: Young males with TLR7 loss-of-function variants and severe COVID-19 represent a subset of male patients contributing to disease susceptibility in up to 2% of severe COVID-19